Inhibition of herpes simplex virus by wedelolactone via targeting viral envelope and cellular TBK1/IRF3 and SOCS1/STAT3 pathways

Development of novel antiherpes simplex virus (HSV) agents with active mechanisms different from nucleoside analogues is of high importance. Herein, we investigated the anti-HSV activities and mechanisms of wedelolactone (WDL) both in vitro and in vivo. Cytopathic effect (CPE) inhibition assay, plaque assay, and western blot assay were used to evaluate the anti-HSV effects of WDL in vitro. The immunofluorescence assay, RT-PCR assay, plaque reduction assay, sandwich ELISA assay, syncytium formation assay, tanscriptome analysis and western blot assay were used to explore the anti-HSV mechanisms of WDL. The murine encephalitis and vaginal models of HSV infection were performed to evaluate the anti-HSV effects of WDL in vivo. WDL possessed inhibitory effects against both HSV-1 and HSV-2 in different cells with low toxicity, superior to the effects of acyclovir. WDL can directly inactivate the HSV particle via destruction of viral envelope and block HSV replication process after virus adsorption, different from the mechanisms of acyclovir. WDL may influence the host genes and signaling pathways related to HSV infection and immune responses. WDL can mainly interfere with the TBK1/IRF3 and SOCS1/STAT3 pathways to reduce HSV infection and inflammatory responses. Importantly, WDL treatment markedly improved mice survival, attenuated inflammatory symptoms, and reduced the virus titres in both HSV-1 and HSV-2 infected mice. Thus, the natural compound WDL has the potential to be developed into a novel anti-HSV agent targeting both viral envelope and cellular TBK1/IRF3 and SOCS1/STAT3 pathways.